We explore the relationship between the technological origins and novelty of inventions on the one hand and their technological impact on the other hand. In particular, we are interested into the technological origins and novelty of breakthrough inventions. By jointly looking at the effects of the origins and novelty on an invention’s average impact, on the likelihood of a very poor invention, and on the likelihood of a breakthrough, we identify some trade-offs researchers face when exploring breakthroughs. For evidence, we consider the US patent record in biotechnology from 1976 to 2001. Our analysis shows that breakthroughs in biotechnology rely more on non-technical and technical prior art, particularly more recent technical prior art, prior art from many different technology fields, and prior art from unfamiliar technology fields. Yet, breakthroughs are less likely to have a dissimilar set of technical prior art citations, as they are more likely to use prior art previously cited by many other inventions. Besides differences in the origins, we find significant differences in the technological novelty. Breakthroughs are more novel in the sense that they are more likely to recombine technological components for the first time in history, particularly more familiar technological components.